Process for the preparation of thiazolidinedione derivatives

ABSTRACT

A process for preparing a compound of formula (I) or a tautomeric form thereof or a pharmaceutically acceptable salt thereof, wherein: A 1  represents a substituted or unsubstituted aromatic heterocyclyl group; R 1  represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; A 2  represents a benzene ring having in total up to five substituents; and n represents an integer in the range of from 2 to 6, which process comprises catalytically reducing a compound of formula (II): wherein A 1 , R 1 , A 2  and n are as defined in relation to formula (I), characterized in that the reduction reaction is carried out using a hydrogen pressure above 20 psi; and thereafter if required forming a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate of the compound of formula (I).

[0001] This invention relates to a novel process and in particular to aprocess for preparing certain substituted thiazolidinedione derivatives.

[0002] European Patent Application, Publication Number 0306228 disclosescertain thiazolidinedione derivatives of formula (A):

[0003] or a tautomeric form thereof or a pharmaceutically acceptablesalt thereof, or a pharmaceutically acceptable solvate thereof, wherein:

[0004] A^(a) represents a substituted or unsubstituted aromaticheterocyclyl group;

[0005] R^(a) represents a hydrogen atom, an alkyl group, an acyl group,an aralkyl group, wherein the aryl moiety may be substituted orunsubstituted, or a substituted or unsubstituted aryl group;

[0006] R^(b) and R^(c) each represent hydrogen or R^(b) and R^(c)together represent a bond;

[0007] A^(b) represents a benzene ring having in total up to fivesubstituents; and

[0008] n′ represents an integer in the range of from 2 to 6.

[0009] EP 0306228 also discloses a process for reducing the compounds offormula (A) wherein R^(b) and R^(c) together represent a bond (the‘benzylidene thiazolidine-2,4-diones’) to the corresponding compounds offormula (A) wherein R^(b) and R^(c) each represent hydrogen (the‘benzylthiazolidine-2,4-diones’). The particular reduction methodsdisclosed in EP 0306228 are dissolving metal methods and catalytichydrogenation methods.

[0010] It has now been discovered that when the catalytic hydrogenationof the benzylidene thiazolidine-2,4-diones is carried out using anelevated pressure of hydrogen that the reaction can be effected with asurprising reduction in the catalytic loading and reaction time and,most surprisingly, produces a significant reduction in by-productformation.

[0011] Accordingly, the present invention provides a process forpreparing a compound of formula (I):

[0012] or a tautomeric form thereof or a pharmaceutically acceptablesalt thereof, or a pharmaceutically acceptable solvate thereof, wherein:

[0013] A¹ represents a substituted or unsubstituted aromaticheterocyclyl group;

[0014] R¹ represents a hydrogen atom, an alkyl group, an acyl group, anaralkyl group, wherein the aryl moiety may be substituted orunsubstituted, or a substituted or unsubstituted aryl group;

[0015] A² represents a benzene ring having in total up to fivesubstituents; and

[0016] n represents an integer in the range of from 2 to 6,

[0017] which process comprises catalytically reducing a compound offormula (II):

[0018] wherein A¹, R¹, A² and n are as defined in relation to formula(I), characterised in that the reduction reaction is carried out using ahydrogen pressure above 20 psi, and thereafter, if required, forming apharmaceutically acceptable salt and/or a pharmaceutically acceptablesolvate of the compound of formula (I).

[0019] Suitably the reaction is carried out at a pressure in the rangeof from 50 to 1500 psi, such as 60 to 1500 psi, 75 to 1500 psi, 200 to1500 psi, 70 to 1000 psi or 200 to 1000 psi, suitably 70 to 1000 psi.

[0020] Examples of reaction pressures include 70, 75, 80, 500 and 1000psi.

[0021] A suitable hydrogenation catalyst is a noble metal catalyst,suitably a palladium catalyst.

[0022] Favoured catalysts are supported noble metal catalysts, such as apalladium-on-carbon catalyst, typically comprising 5% to 10% ofpalladium.

[0023] A preferred catalyst is a 10% palladium-on-carbon catalyst.

[0024] Catalyst loadings (expressed as w/w% of catalyst to substrate) inthe reaction are typically in the range of from 5 to 100%, usually 10 to50% and preferably 25 to 50%.

[0025] The reaction may be carried out using any suitable solvent suchas acetic acid, or an alkanol, such as methanol or ethanol, preferablyadmixed with an aqueous mineral acid such as hydrochloric acid; ortetrahydrofuran, preferably admixed with an aqueous mineral acid such ashydrochloric acid. Preferably the solvent is acetic acid or aqueousacetic acid, for example a 4:1 acetic acid:water mixture.

[0026] The reaction is carried out at a temperature which provides asuitable rate of formation of the required product, suitably at anelevated temperature, preferably above 70° C., for example in the rangeof from 80° C. to 115° C.

[0027] The compounds of formula (I) are isolated from the reaction andsubsequently purified by use of conventional isolation and purificationmethods such as chromatography and crystallization/recrystallization.

[0028] The suitable, apt, favoured and preferred values of the variablesA¹, A², R¹ and n in formulae (I) and (II) are as defined in relation toformula (I) of EP 0306228.

[0029] A most preferred value of A¹ is a 2-pyridyl group.

[0030] A most preferred value of A² is a moiety of formula:

[0031] A most preferred value of R¹ is a methyl group.

[0032] A most preferred value of n is 2.

[0033] A most preferred value of formula (I) is5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione,or a tautomeric form thereof or a salt thereof, or a solvate thereof.

[0034] Crystalline5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedioneis isolated from the present reaction and as such forms a further aspectof the present invention. A suitable crystallization/recrystallizationsolvent is acetic acid/denatured ethanol, the crystallization isfavourably effected from refluxing, solvent which is allowed to coot toprovide the required compound.

[0035] A most preferred value of formula (II) is5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedioneor a tautomeric form thereof or a salt thereof, or a solvate thereof.

[0036] Suitable salts are pharmaceutically acceptable salts.

[0037] Suitable pharmaceutically acceptable salts include metal salts,such as for example aluminium, alkali metal salts such as sodium orpotassium, alkaline earth metal salts such as calcium or magnesium andammonium or substituted ammonium salts, for example those with loweralkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine or quinoline.

[0038] In addition should be mentioned those pharmaceutically acceptablesalts provided by pharmaceutically acceptable acids including mineralacids, including salts provided by mineral acids, such as hydrobromic,hydrochloric and sulphuric acids, and organic acids, such asmethanesulphonic, tartaric and maleic acids, especially tartaric andmaleic acid. A preferred salt is a maleate salt.

[0039] Suitable solvates are pharmaceutically acceptable solvates, suchas hydrates.

[0040] The compounds of formula (II) are prepared according to knownmethods, for example by use of the appropriate method disclosed in EP0306228. The contents of EP 0306228 are incorporated herein byreference.

[0041] The following example illustrates the invention but does notlimit it in any way.

EXAMPLE Reduction of(Z)-5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedioneto5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione.

[0042] To a solution of(Z)-5-{[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}2,4-thiazolidinedione(123 kg) in glacial acetic acid (1232 L) is added 10% palladium oncharcoal (Johnson-Matthey type 87L, 123 kg, catalyst contains ˜50% w/wwater and hence the catalyst loading was 50% w/w). The resulting mixtureis hydrogenated at 70-80 p.s.i. hydrogen pressure at about 95° C. Afterthe starting material is consumed (15-20 hours), the reaction mixture iscooled to about 65° C. and the catalyst is removed by filtration. Theresulting solution is concentrated under reduced pressure to low volumeand the residue is dissolved in denatured ethanol (1000 L) at 60° C. Thesolution is heated to reflux and then cooled to ambient temperature toeffect recrystallisation. The product,5-{[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione,is isolated by filtration, and dried in vacuo at 45° C. Typical yieldsare 70-80%.

[0043] Effect of Change of Reaction Pressure

[0044] The above reaction can be preformed over a range of pressuresresulting in a significant reduction in reaction time and catalystloading, as shown below. Reaction number Conditions Reaction Time(hours.) 1 (75 psi, 50% catalyst) 15-20 2 1000 psi, 50% catalyst <2 31000 psi, 25% catalyst   7 4 500 psi, 50% catalyst   4 5 500 psi, 25%catalyst ca. 12

1. A process for preparing a compound of formula (I):

or a tautomeric form thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: A¹ represents a substituted or unsubstituted aromatic heterocyclyl group; R¹ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; A² represents a benzene ring having in total up to five substituents; and n represents an integer in the range of from 2 to 6, which process comprises catalytically reducing a compound of formula (II):

wherein A¹, R¹, A² and n are as defined in relation to formula (1), characterised in that the reduction reaction is carried out using a hydrogen pressure above 20 psi; and thereafter if required forming a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate of the compound of formula (I).
 2. A process according to claim 1, wherein the reaction is carried out using a hydrogen pressure in the range of from 50 to 1500 psi, 60 to 1500 psi, 75 to 1500 psi, 70 to 1000 psi or 200 to 1500 psi.
 3. A process according to claim 1 or claim 2, wherein the reaction hydrogen pressure is in the range of from 70 to 1000 psi.
 4. A process according to any one of claims 1 to 3, wherein the reaction hydrogen pressure is 70, 75, 80, 500 or 1000 psi.
 5. A process according to any one of claims 1 to 4, wherein the hydrogenation catalyst is a 10% palladium-on-carbon catalyst.
 6. A process according to any one of claims 1 to 5, wherein the catalyst loading is 5 to 100%, (% w/w of catalyst to substrate).
 7. A process according to any one of claims 1 to 6, wherein the reaction solvent is acetic acid, aqueous acetic acid, an alkanol, an alkanol admixed with an aqueous mineral acid, tetrahydrofuran or tetrahydrofuran admixed with an aqueous mineral.
 8. A process according to claim 7, wherein the reaction solvent is acetic acid.
 9. A process according to any one of claims 1 to 8, wherein the reaction temperature is in the range of from 80° C. to 115° C.
 10. A process according to any one of claims 1 to 9, wherein the compound of formula (II) is 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedione, or a tautomeric form thereof or a salt thereof, or a solvate thereof, and the compound of formula (I) is 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione, or a tautomeric form thereof or a salt thereof, or a solvate thereof. 